Histiocytosis Medication

Updated: Jan 11, 2023
  • Author: Cameron K Tebbi, MD; Chief Editor: Vikramjit S Kanwar, MBBS, MBA, MRCP(UK)  more...
  • Print

Medication Summary

The aim of therapy in histiocytosis is to relieve clinical symptoms and prevent complications of the disease. For single-system disease (eg, of the skin or bone), no therapy or only local therapy may be necessary, although further treatment may be needed in certain circumstances. [46, 62, 283, 284, 12]

Localized skin lesions, especially in infants, can spontaneously regress. If treatment is required, topical corticosteroids may be tried. Use of extemporaneously prepared topical 0.02% nitrogen mustard has also been advocated, but concerns of its mutagenic activity, especially in children, should be considered. [284, 74, 285] This agent, initially used systemically, appears to provide rapid response within 10 days [286] with minimal adverse effects, such as contact allergy. Scarring at the site of the lesion is thought to be due to the disease and not therapy. [285] In one study, skin lesions promptly healed in 14 of 22 children, and two had partial responses. [286] Low-dose radiation therapy to the local lesions is often effective but is rarely needed. For unresponsive skin lesions, low-dose mild systemic therapy can be used.

Chemotherapy for multisystemic disease with local or constitutional symptoms is used. [284] Single agents or adjuvant use of several chemotherapeutic agents and/or biologic-response modifiers may be effective. Published therapies include corticosteroids, vinca alkaloids, antimetabolites-nucleoside analogs, immune modulators such as cyclosporine, [287] antithymocyte globulin, [287] biologic-response modifiers such as interleukin (IL)-2 and interferon alpha (INF-alpha), [288] cellular treatment, and exchange transfusion. [289] Most reports of treatment modalities lack controls, with most authors citing the rarity of the disease as justification for this deficiency. [290, 77]

Phase I and II investigational therapies have included the use of single agents such as dabrafenib, GSK2110183, cladribine, [291] imatinib mesylate, [292] vemurafenib, [192] clofarabine, [293] and alemtuzumab [294] or combinations of agents such as alemtuzumab plus cyclophosphamide and busulfan plus fludarabine plus melphalan. Longer duration of therapy appear to improve the outcome in multisystem LCH. [295]

Single-agent therapy

Purine analogs with activity for treatment of Langerhans cell histiocytosis (LCH) include 2-chlorodeoxyadenosine (2CdA; cladribine [Leustatin]) and 2-deoxycoformycin (2CDF; pentostatin; [296, 297, 298, 299, 300, 301, 302] 2CdA has been found to be particularly toxic to monocytes. [297, 298] Justification for the use of 2CdA is that some histiocytes are derived from monocytes. [208] In a review of 15 patients with multiorgan involvement receiving 2CdA and 2 receiving 2CDF, 6 had complete responses, 3 had partial responses, 5 had no response, and 1 died early. Fourteen had previously received significant treatments. [296]

As a single agent, cyclosporine has been used in pretreated patients with advanced Langerhans cell histiocytosis. Cyclosporine, a cyclic undecapeptide immunosuppressant of fungal origin, inhibits immune responses. The proposed mechanism of action is blockage of the transmission and synthesis of lymphokines, such as IL-2 and INF (ie, INF-alpha inhibition of the accessory cell function of Langerhans cells and reduced capacity of dendritic cells to enhance mitogenic stimulation of lymphocytes). Cyclosporine is postulated to disrupt abnormal cytokine-dependent activation of lymphocytes and histiocytes in the liver, spleen, lymph nodes, and bone marrow. The activation of lymphocytes is presumed to be secondary to uncontrolled proliferation of Langerhans cells. Furthermore, cyclosporine can inhibit cytokine-mediated cellular activation that potentially contributes to phagocytosis and disease progression. [287]

Cytosine arabinoside (cytarabine, ARA-C, Cytosar U), an antimetabolic chemotherapy agent, has been used for treatment of children and adults with Langerhans cell histiocytosis. The mechanism of action of this agent, has been used for treatment of children and adults with LCH. The mechanism of action of this agent is conversion to cytosine arabinoside triphosphate (Ara-CTP) by deoxycytidine kinase and other nucleotide kinases which results in cellular arrest in the S phase of inhibits RNA and DNA polymerases and nucleotide reductase enzymes necessary for DNA synthesis.

Cytosine arabinoside is converted to its inactive form, uracil arabinoside, by pyrimidine nucleoside deaminase. Because of its capability to cross the blood brain barrier, has efficacy in cases with CNS involvement. Cytosine arabinoside converts to uracil arabinoside (ARA-U) by pyrimidine nucleoside deaminase and is excreted mostly (80%) in the urine. This agent has been successfully used in single form or in combination in treatment of children and adults with LCH, including CNS involvement. [303, 304, 305, 306]


This agent is a purine nucleoside metabolic inhibitor. Clofarabine is metabolized intracellularly to the 5’-monophosphate metabolism by deoxycytidine kinase and monokinase and diphosphokinase to the active 5’-triphosphate metabolite. This agent inhibits DNA synthesis by several mechanisms. This includes decreasing cellular deoxynucleotide substrate and deoxycytidine. Clofarabine inhibits DNA synthesis by reducing cellular deoxynucleotide phosphate pool via inhibition of ribonucleotide reductase and termination of DNA chain elongation.

Furthermore, it inhibits DNA repair through incorporation into the DNA chain by competitive inhibition of DNA polymerases. Clofarabine 5’-triphosphate disrupts repair by incorporation into the DNA chain during the repair process. It also disrupts integrity of mitochondrial membrane resulting in release of the proapoptotic mitochondrial proteins, cytochrome C, and apoptosis-inducing factor. This results in programmed cell death. After intravenous administration, clofarabine becomes bound to plasma proteins (47%) mainly albumin. The half-life of this agent, in pediatric patients, is 5.2 hours. Approximately, 49-60% of clofarabine is excreted in the urine unchanged.

Clofarabine, as a single agent and in combination, appears to be active in treatment of LCH, including advanced forms, not responding to the conventional therapies. [307]

In one study of 6 pediatric patients with multisystem LCH, this agent had shown promising results with significant side effects. In another report of 18 refractory patients who had previously received a median of three chemotherapeutic agents for Langerhans cell histiocytosis, juvenile xanthogranuloma and Rosai-Dorfman disease, 17 responses were noted after two to four cycles of therapy with clofarabine. These patients were treated with two to eight cycles of 25 mg/m2 for 5 days of clofarabine. Complete responses were seen in 61% and partial response in 22% with the remaining patients being on therapy at the time of the report. Neutropenia, vomiting, and infections were the major short term toxicities.

Partial and complete responses have been recorded in a small number of patients. Patients with partial response had achieved a complete response with prednisone and vinblastine chemotherapy. Cyclosporine A has also been used in familial erythrophagocytic lymphohistiocytosis (FEL). In one report of 2 children whose disease was resistant to steroids and etoposide, durable remission was obtained with this agent. [308]

INF-alpha had some effect in anecdotal cases of Langerhans cell histiocytosis. [288, 309]

Treatment of multifocal relapsing and resistant bone lesions in LCH is challenging. Langerhans cells are capable of releasing cytokines, which are potent activators of osteoclasts and can result in the lytic lesions seen in the disease. Pamidronate, a bisphosphonate agent, has been reported to induce response or result in disease stability in a small group of patients. [310]

Multiagent therapy

Most chemotherapy agents for the treatment of Langerhans cell histiocytosis are used in combination. The length of therapy is arbitrarily chosen. In some studies, patients were stratified by risk factor. [311] Use of a combination of cytarabine arabinoside (Ara-C), vincristine, and prednisolone to treat disseminated Langerhans cell histiocytosis with organ dysfunction has been reported.

In a study of 18 pediatric patients with Langerhans cell histiocytosis and multiorgan involvement, 8 had additional organ dysfunction; 8 of 10 patients with organ involvement achieved complete remission. [312] Five of 8 patients with additional dysfunction achieved complete remission. Four (22%) of 18 patients developed diabetes insipidus. Two with organ dysfunction died at the time of the report. The regimen was described as being mildly toxic and relatively well tolerated. In this regimen, cytarabine (100 mg/m2/d for 4 consecutive days), vincristine (1.5 mg/m2 on day 1), and prednisone (40 mg/m2/d for 4 wk followed by 20 mg/m2 for 20 d) were administered. The combination of vincristine and cytarabine was repeated every other week for 4 weeks. Thereafter, the interval was extended by 1 week until this combination was administered every 6 weeks, until complete remission was achieved (4-16 wk).

In a multicenter study in 1983-1988, Italian investigators assigned 70 patients with biopsy-proven Langerhans cell histiocytosis into good-prognosis or poor-prognosis groups, depending on their organ dysfunction. [313] Sixteen patients with limited disease were treated with surgery alone, 5 received immunotherapy with thymus extract then chemotherapy, and 49 patients received chemotherapy with vinblastine (5.5 mg/m2/wk for 3 mo).

Poor responders in this group were then treated with doxorubicin (20 mg/m2 intravenously for 2 d every 3 wk for 3 mo). Patients who did not improve with this regimen were administered etoposide (200 mg/m2 intravenously) for 3 consecutive days every 3 weeks for at least 3 months or until their disease progressed.

The poor-prognosis group (11 patients) received doxorubicin (20 mg/m2 on days 1 and 2), prednisone (40 mg/m2 by mouth on days 1-29), vincristine (1.5 mg/m2 intravenously once a week for 4 wk starting on day 8), and cyclophosphamide (400mg/m2 on days 15 and 29 for 9 courses).

Only 1 of 10 patients with good prognosis had a favorable response during therapy with thymus extract. Of 54 patients receiving chemotherapy (49 as first-line treatment), 34 achieved complete remission with vinblastine, and 8 had a recurrence after 4-22 months. Of 15 patients achieving remission with etoposide, 1 had a relapse 10 months after therapy. In 11 patients with poor prognoses, 7 had progressive disease, and 6 died within 9 months of diagnosis. Organ dysfunction appeared to significantly affect survival, with only 46% of patients surviving for 12 months. The main complication was diabetes insipidus, which occurred in 20% of patients. The overall incidence of disease-related disabilities was 48%.

In the Austrian and German DAL-HX 83/90 study, patients were stratified into 3 groups: those with multifocal bone disease (group A), those with soft-tissue involvement but without organ dysfunction (group B), and those with organ dysfunction (group C). [311] Induction therapy consisted of etoposide (60 mg/m2/d for 5 d on days 1-5, followed by weekly dosing of 150 mg/m2), prednisone (40 mg/m2 on days 1-28), and vinblastine (6 mg/m2 starting at week 3 of therapy). Maintenance therapy was risk related and consisted of vinblastine, 6-mercaptopurine, and prednisone in all patients, with etoposide added in group B and methotrexate and etoposide added in group C. Mortality rates for groups A, B, and C were 8%, 9%, and 38%, respectively.

An organized international approach to LCH has been successful. [45, 284, 314] Using the Histiocyte Society’s Langerhans cell histiocytosis I protocol, [315, 283] investigators prospectively and randomly assigned patients with multisystemic Langerhans cell histiocytosis who met criteria based on standard diagnostic evaluation. [62] Patients received vinblastine (6 mg/m2 intravenously weekly for 24 wk) or etoposide (150 mg/m2 intravenously on 3 consecutive days every 3 wk for 24 wk). All patients received methylprednisolone (30 mg/kg intravenously for 3 consecutive days [maximum daily dose of 1 g]). Of the 447 patients who were registered from various countries, 192 had multisystemic disease, and 136 were randomly assigned (72 to the vinblastine arm and 64 to the etoposide arm).

Patients were evaluated at predetermined intervals. Responses at 6 weeks appeared to differentiate responders from nonresponders, who had poor outcomes. Neither the patients’ ages nor the number, type, or dysfunction of the organs differentiated the groups. At 6 weeks, 51 (50%) of 103 patients achieved a complete response or substantial disease regression, whereas 32 (31%) had stable disease or partial or mixed responses. Disease progression was reported in 19 patients. At 26 months, the mortality rate was 18%. Among the patients who died, 4 had an initial response, 5 had intermediate responses, and 9 had initial nonresponses.

The protocol allowed nonresponders to switch to another treatment arm. Only 34% of patients who had switched had favorable results. Disease recurrence was observed in 11 patients who received vinblastine and in 8 who received etoposide. The 2 arms were statistically similar in terms of initial responses, recurrences, and mortality rates. The overall probability of diabetes insipidus was 42%.

The randomized Langerhans cell histiocytosis II study of the Histiocyte Society was performed to compare the effects of oral prednisone with vinblastine (with or without etoposide) in patients with multisystemic disease. Patients were divided into low- or high-risk groups. All patients received prednisone (40 mg/m2/d for 28 d with weekly reduction afterward) and vinblastine (6 mg/m2 intravenously weekly for 6 wk). The low-risk group received continuation therapy with vinblastine (6 mg/m2 during weeks 9, 12, 15, 18, 21, and 24), as well as 5-day pulses of prednisone during the same weeks. Patients in the low-risk group were excluded from randomization.

Patients in the high-risk group were randomly assigned to treatment A or B. Treatment consisted of an initial 6 weeks of therapy with prednisolone and weekly vinblastine and continuation therapy, pulses of vinblastine and/or oral prednisone as in the low-risk group, and daily doses of 6-mercaptopurine (50 mg/m2 during weeks 6-24). Treatment B was the same as treatment A, with the addition of etoposide (150 mg/m2 administered on day 1 of weeks 9, 12, 15, 18, 21, and 24). Results of this protocol have not yet been published.

The Langerhans cell histiocytosis III study of the Histiocyte Society indicated that in children with multi-system Langerhans cell histiocytosis, the use of intense, prolonged initial treatment can produce an overall 5-year survival rate of 84%. High-risk patients in the study underwent 12 months of treatment, receiving one or two 6-week courses of chemotherapy and a subsequent course of milder continuation therapy, with the first 12 weeks of treatment appearing to be critical to patient outcomes. [316]

Treatment for recurrent or refractory disease

The severity of the recurrent disease often dictates the type of therapy that is most likely to be helpful. For example, recurrence of an isolated bone lesion can often be treated with nonsteroidal anti-inflammatory drugs (NSAIDs) or intralesional steroid injections. When bone lesions are multiple and cause clinically significant morbidity, systemic therapy can be helpful. In such circumstances, patients often respond to the same drugs that they previously received, such as vinblastine and/or corticosteroids.

A retrospective study by Sedky et al indicated that in children with Langerhans cell histiocytosis, those who suffer multiple reactivations of the disease respond well to repeated use of first-line treatment, with or without methotrexate. The study, which had a median follow-up period of 42 months, involved 80 pediatric patients with the condition who were treated according to the Langerhans cell histiocytosis III protocol; 25 patients experienced reactivation, including 5 who suffered multiple reactivations. [317]

Extensive recurrence of skin disease, including refractory perianal or vulvar involvement, often requires systemic chemotherapy.

When patients do not have an early (ie, by 6 wk of therapy) response to vinblastine, corticosteroids, methotrexate, 6-mercaptopurine, or even etoposide, alternate therapies should be administered. Although several immunomodulatory agents, such as cyclosporine, have been used in patients with refractory disease, the results have been inconsistent. Cytotoxic chemotherapy often needs to be administered as well. Vemurafenib has been reported to be a highly effective agent for the treatment of adults with multisystemic and refractory LCH and polyostotic sclerosing histiocytosis (Erdheim-Chester disease).

Several studies, including an international phase II trial, demonstrated notable activity associated with 2CdA. This agent was originally used to treat patients with refractory hairy-cell leukemia and chronic lymphocytic leukemia. Response rates were more than 50%. Because 2CdA has antiproliferative effects on lympholytic and histiocytic cells, it is a potentially ideal drug to use in Langerhans cell histiocytosis, which is characterized by reactive lymphocytic and dendritic and macrophage components. Response rates to 2CdA have been particularly good in patients with extensive skin and bone disease, and in some patients with pulmonary involvement. Overall response rates have been about 30-40% in children. In a study with a small number of adults, the response rate was less than 70%. In 2 reports, a combination of 2CdA and Ara-C seemed to have major effects in a small group of children with refractory disease, but clinically significant grade 4 toxicities and a sepsis-related death were reported. [303, 318]

For some patients whose disease does not respond to 2CdA alone, the combination of 2CdA and high-dose cytarabine has been effective. A similar regimen has also been effective in patients with relapses of acute myelogenous leukemia. Until additional information is obtained with this drug combination, the true response rate and the duration of response are difficult to determine.

Other approaches to the treatment of patients with refractory Langerhans cell histiocytosis that are being tested or developed and include agents such as thalidomide, which is used to inhibit tumor necrosis factor (TNF)-alpha and INF-gamma production. [319] (INF-gamma is a cytokine produced by a subgroup of lymphocytes to regulate immune responses.) In some studies, only patients with low-risk disease were likely to respond to thalidomide, whereas high-risk patients with organ involvement were not. [320, 321] Emapalumab, a monoclonal antibody that also inhibits INF-gamma, is under investigation for the treatment of hemophagocytic lymphohistiocytosis (HLH).

Further recognition of NF-kappaB pathway may improve the success of targeted therapy for Langerhans cell histiocytosis. [322]

Targeting humanized antibodies against lineage-specific antigens, such as CD1a antigens on Langerhans cell histiocytosis cells, is another treatment being developed. The application of inhibitors of activated cytokine receptors and their downstream signal-transduction pathways is also an important area of future therapeutic trials. Although hematopoietic stem-cell transplantation has been successful in some patients with refractory Langerhans cell histiocytosis, identifying patients who might benefit from such high-risk therapy is difficult, and this treatment is associated with significant acute and chronic complications.

In some studies, children with multisystem LCH and risk organ involvement who had not responded to conventional therapies underwent a reduced intensity conditioning regimen (RIC) followed by allogenic stem cell transplantation, which was associated with lower transplant-related morbidity and mortality as well as an improved outcome. [16]

Specific therapies, including monoclonal antibodies against the CD1a or CD52 epitopes found on Langerhans cells, are emerging. [306]

Local therapy with various agents has been reported. Intralesional infiltration with corticosteroids for treatment of localized LCH has been advocated. [323]

Myeloablative therapy followed by bone-marrow or stem-cell transplantation in disease refractory to the conventional therapy has been reported. [324] However, reporting of positive results are likely to bias such reports.

Intravenous immunoglobulin has been used to treat neurodegenerative LCH. However, to the authors’ knowledge, no formal study has been done to conclusively affirm the benefit of such a treatment. For FHL treatment, a combination of antithymocyte globulin, steroids and cyclosporin has been used. [325]

The need to develop effective treatments and, ultimately, strategies to prevention progressive fibrosis of the lung, sclerosing cholangitis, and fibrosis of the liver, and the neurodegenerative pattern of CNS involvement is immense. Additional clinical trials are needed to determine whether agents such as 2CdA or specific inhibitors of fibrosis can improve the outcomes of patients with these complications.